The percentage of population over the age of 65 increases in most developed countries, and so does the incidence of cataracts in this high risk age group. A cataract is a progressive clouding of the natural crystalline lens of the eye which obstructs the passage of light to the retina. Functional blindness can occur when the lens becomes substantially opaque.
As treatment for cataracts surgical removal of the lens from the lens capsule and insertion of an intraocular lens is commonly indicated. Only in the United States well over 1 million people have cataract surgery every year to remove a clouded natural lens, and over 95% of the patients involved have-an intraocular lens implanted to allow them to clearly see again. As the retirement-age population increases., the incidence of such procedure is also expected to increase.
One of the most common complications of this surgical procedure is cellular proliferation in the capsular bag, with subsequent capsule wrinkling and opacification. "Secondary cataract" formation is a proliferation and transformation of cells on the lens capsule occurring in approximately 17-30% of patients receiving intraocular lenses within the year following surgery. In subsequent years, the percentage of patients experiencing such ingrowth increases. In recent studies, the incidence of secondary cataract formation has been reported to be 15-50% in adult patients with a 2 to 7 year follow up, and nearly 100% in the pediatric age group. [See, for example, Maltzman et al., Ophthalmic Surgery 20(5), 321-324 (1989); Nishi, O., J. Cataract Refractive Surgery 12, 510-552 (1986); Henahan, S., Ophthalmology Times 13(1), 10, 12 Dec. 15 (1988).]
While the causative factors involved in secondary cataract formation are unknown, the process is characterized by:
1. lens epithelial cell migration, proliferation and myoblastic transformation;
2. collagen production by these epithelial cells and fibrous membrane formation; and
3. wrinkling of the posterior capsule due to contraction of myoblastic cells [McDonnell et al., Ophthalmology 90, 1548-1553 (1983); McDonnel et al., Ophthalmology 91, 853-856 (1984)].
Complete removal or destruction of all lens epithelial cells in the lens capsule and control of inflammatory cells is imperative if such complications are to be avoided. During routine extracapsular cataract extraction, with or without lens insertion, every effort is made to completely remove all lens cells and control inflammation. However, these efforts, to date, have not been entirely successful primarily due to the fragmentation of the lens tissue during surgical removal and the difficulty of removing every lens-related cell.
Current therapy for the prevention of secondary cataract formation includes the use of postoperative steroids and refinements in surgical techniques (such as Aniz technique) to decrease breakdown of the blood aqueous barrier. The preferred method is Neodymium YAG Laser Capsulotomy which is not without complications. The main intraoperative complication of this technique is damage to the intraocular lens optic, occurring in about 20% of cases in a large survey [Stark et al., Opthalmology 92, 209-212 (1985)]. While usually clinically insignificant, a dense pattern of so called "lens dings" can affect visual acuity. Other operative complications include rupture of the anterior hyaloid and vitreous prolapse, corneal edema, iris bleeding and damage, transient elevation of intraocular pressure, cystoid macular edema, retinal detachment and pupillary-block glaucoma.
In search of methods associated with extracapsular cataract surgery which would prevent or delay the onset of secondary cataract formation, various approaches are known in the art. Modifications in the design of intraocular lenses (IOLs) have been .reported to bring certain results. For example, contact between the optic of an IOL and the posterior capsule has been described to maintain the clarity of the central capsule.
Other attempts to avoid or delay secondary cataract formation focus on cellular kill, using cytotoxic agents, such as antiproliferatives (methotrexate, retinoic acid); immunotoxins (human lens epithelial surface antibody conjugated to Ricin A, basement membrane collagen conjugated to methotrexate); chemical debridement (EDTA and trypsin); mechanical debridement (ultrasound, cryotherapy).
Roy et al., Medical Journal 175-178 (1979) describe animal studies concerning the use of vincristine and vinblastine to inhibit subcapsular epithelial cell growth. Although they had a direct inhibitory effect on cell mitosis, these highly toxic chemicals were found to inhibit corneal wound healing and had deleterious side-effects on the cornea and iris. Radiation applied the second day after surgery was reported to be more effective, but the risk of radiation therapy in human eye is prohibitive as to its application.
According to the Canadian Patent No. 1,178,206 proliferation of remnant lens epithelial cells is prevented by an effective dose of the mitotic inhibitor methotrexate or retinoic acid or a combination of the two inhibitors. Osmotically balanced solutions of the same compounds for preventing posterior lens capsule opacification are disclosed in the U.S. patent Specification No. 4,657,930.
A different approach to the inhibition of remnant lens epithelial cells after extracapsular extraction is the use of monoclonal antibodies specific to residual lens epithelial cells which can be used to destroy these cells selectively, without damage to other parts of the eye at the time of the cataract removal (see U.S. Pat. No. 4,432,751).
Immunotoxins comprising antibodies specific to the proliferative cells conjugated to an antiproliferative agent, are disclosed in the U.S. patent application Ser. No. 168,697, filed Mar. 16, 1988, assigned to Allergan, Inc.
Although some of the prior art methods have promising results, they either employ highly toxic chemicals or dangerous radiation treatments, or use antibodies and antibody-conjugates, which have to be produced in a lengthy and rather expensive procedure. Accordingly, there is a great need for an effective and simple procedure for ensuring the complete removal and/or destruction of lens cells and other proliferative cells from the lens capsule prior to implantation of the intraocular lens.
In addition to the removal of natural lens due to cataract formation, there are additional ocular surgical procedures where proliferation of remnant cells is to be avoided. Such procedures include retinal reattachment procedures and vitrectomy, that are being performed at ever increasing rates.
Surgical replacement of the vitreous, and scleral buckling procedures are commonly indicated as treatment for retinal tears, traction retinal detachment and opacities in the vitreous from various causes including but not limited to, diabetic retinopathy, proliferative vitreoretinopathy, vitreous hemorrhage, endophthalmitis, etc. In these procedures, retinal pigment epithelial cells, fibroblasts and glial cells create contractile cellular membranes and thereby cause traction retinal detachment.
Proliferative vitreoretinopathy is the major cause of failure after retinal reattachment surgery and vitrectomy. This disorder is characterized by the formation of cellular membranes within the vitreous cavity which cause traction retinal detachments.
Proliferative vitreoretinopathy generally results from migration of the retinal pigment epithelial cells, fibroblasts and glial cells into the vitreous cavity. Any cellular proliferation in the vitreous is to be avoided if proliferative vitreoretinopathy is to be prevented. To illustrate the seriousness of this problem, in a series of 1088 eyes, proliferative vitreoretinopathy was the most common cause of failure (27%) following retinal detachment surgery.
Accordingly, there is a great need for an effective and simple procedure for avoiding cellular proliferation following retinal reattachment procedures (with or without vitrectomy). The approaches employed so far for complete removal and/or destruction of migrating retinal pigment epithelial cells, were not entirely successful. Similar problems are encountered in other, non-ocular surgical procedures. For example, the long-term success of the surgical removal of certain tumors, e.g. breast tumors, is greatly dependent on how efficiently all tumor-related cells can be removed and/or destroyed. Not sufficient control of tumor cell proliferation may result in the reoccurrence of tumor.
Therefore, there is a great need for a method that could reliably prevent or, at least, limit regrowth of cells following such surgeries.